論文 - 栗原　俊英

Retinal phototoxicity in a novel murine model of intraocular lens implantation.

栗原 俊英

Mol Vis. （MOLECULAR VISION）  15 （ 290 ） 323 - 329 2009年12月

研究論文（学術雑誌）, 査読有り,  ISSN  1090-0535

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Purpose: To establish a novel murine intraocular lens (IOL) implantation model to study the protective effects of colored-IOLs against retinal phototoxicity.
Methods: Two-millimeter diameter IOL buttons were created from IOLs for clinical use. Extra-capsular crystalline lens extraction and IOL implantation were performed in BALB/c mice using a technique similar to human cataract surgery. For light exposure experiments, mice were exposed to 5,000 LUX of white light for 24 h on the day after surgery. To investigate the protective effects of yellow IOL against light exposure, ERG measurements were conducted in vivo, followed by TdT-mediated dUTP Nick-End Labeling (TUNEL) and outer nuclear layer (ONL) thickness measurement of retinal tissue in yellow or clear IOL-implanted mice and control mice without surgery.
Results: IOLs were successfully implanted in all animals, and IOL buttons without haptics were well stabilized in the capsular bag. Murine eyes developed posterior capsule opacification (PCO) after IOL implantation by postoperative day 5 at the latest. In contrast to the clear IOL-implanted animals stimulated by light exposure, the yellow IOL-implanted animals had significantly reduced numbers of TUNEL-positive cells and retained thickness of the ONL. The ERG showed that yellow IOL implantation prevents a decrease of amplitude in both the a-wave and b-wave compared with clear IOL implantation.
Conclusions: We established a new animal model of IOL implantation and demonstrated the protective effects of colored-IOL against retinal phototoxicity after cataract surgery.

Bilateral acute functional disturbance in the retina following placental abruption.

栗原 俊英

Jpn J Ophthalmol. （SPRINGER TOKYO）  53 （ 6 ） 663 - 665 2009年11月

研究論文（学術雑誌）, 査読有り,  ISSN  0021-5155

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Involvement of Hyaluronan and Its Receptor CD44 with Choroidal Neovascularization.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  50 （ 9 ） 4410 - 4415 2009年09月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV).
METHODS. Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)-choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an antiCD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury.
RESULTS. The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody-based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice.
CONCLUSIONS. These results indicate a significant role of HA and its receptor CD44 in the development of CNV. (Invest Ophthalmol Vis Sci. 2009;50:4410-4415) DOI: 10.1167/iovs.08-3044

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Prevention of Ocular Inflammation in Endotoxin-Induced Uveitis with Resveratrol by Inhibiting Oxidative Damage and Nuclear Factor-kappa B Activation.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  50 （ 7 ） 3512 - 3519 2009年07月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU).
METHODS. EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappa B p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay.
RESULTS. Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappa B P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol.
CONCLUSIONS. Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappa B activation. (Invest Ophthalmol Vis Sci. 2009; 50: 3512-3519) DOI: 10.1167/iovs.08-2666

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Neuroprotective Effect of an Antioxidant, Lutein, during Retinal Inflammation.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  50 （ 3 ） 1433 - 1439 2009年03月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. Lutein has been the focus of recent study as a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate, with the use of a mouse endotoxin-induced uveitis (EIU) model, the neuroprotective effects of lutein against retinal neural damage caused by inflammation.
METHODS. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Each animal was given a subcutaneous injection of lutein or vehicle three times: concurrently with and 3 hours before and after the LPS injection. Analysis was carried out 24 hours after EIU induction. Levels of rhodopsin protein and STAT3 activation were analyzed by immunoblotting. Lengths of the outer segments of the photoreceptor cells were measured. Dark-adapted full-field electroretinograms were recorded. Oxidative stress in the retina was analyzed by dihydroethidium and fluorescent probe. Expression of glial fibrillary acidic protein (GFAP) was shown immunohistochemically.
RESULTS. The EIU-induced decrease in rhodopsin expression followed by shortening of the outer segments and reduction in a-wave amplitude were prevented by lutein treatment. Levels of STAT3 activation, downstream of inflammatory cytokine signals, and reactive oxygen species (ROS), which are both upregulated during EIU, were reduced by lutein. Pathologic change of Muller glial cells, represented by GFAP expression, was also prevented by lutein.
CONCLUSIONS. The present data revealed that the antioxidant lutein was neuroprotective during EIU, suggesting a potential approach for suppressing retinal neural damage during inflammation. (Invest Ophthalmol Vis Sci. 2009; 50: 1433-1439) DOI: 10.1167/iovs.08-2493

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New retractor capable of aspirating fluids during scleral buckling surgery.

栗原 俊英

Retina. （LIPPINCOTT WILLIAMS & WILKINS）  29 （ 10 ） 1542 - 1544 2009年01月

研究論文（学術雑誌）, 査読有り,  ISSN  0275-004X

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Roles of STAT3/SOCS3 pathway in regulating the visual function and ubiquitin-proteasome-dependent degradation of rhodopsin during retinal inflammation.

栗原 俊英

J Biol Chem. （AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC）  283 （ 36 ） 24561 - 24570 2008年09月

研究論文（学術雑誌）, 査読有り,  ISSN  0021-9258

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Inflammatory cytokines cause tissue dysfunction. We previously reported that retinal inflammation down-regulates rhodopsin expression and impairs visual function by an unknown mechanism. Here, we demonstrate that rhodopsin levels were preserved by suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of STAT3 activation. SOCS3 was expressed mainly in photoreceptor cells in the retina. In the SOCS3-deficient retinas, rhodopsin protein levels dropped sooner, and the reduction was more profound than in the wild type. Visual dysfunction, measured by electroretinogram, was prolonged in retina-specific SOCS3 conditional knockout mice. Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency. Interleukin 6, one of the inflammatory cytokines found during retinal inflammation, activated STAT3 and decreased rhodopsin protein in adult retinal explants. This was enhanced by inhibiting SOCS3 function in vitro, indicating that rhodopsin reduction was not a secondary effect in the mutant mice. Interestingly, in the inflamed SOCS3-deficient adult retina, rhodopsin decreased post-transcriptionally at least partly through ubiquitin-proteasome-dependent degradation accelerated by STAT3 activation and not transcriptionally as in the developing retina, on which we reported previously. A STAT3-dependent E3 ubiquitin ligase, Ubr1, was responsible for rhodopsin degradation and was up-regulated in the inflamed SOCS3-deficient retinas. These results indicate that in wild-type animals, a decrease in rhodopsin during inflammation is minimized by endogenous SOCS3. However, when STAT3 activation exceeds some threshold beyond the compensatory activity of endogenous SOCS3, rhodopsin levels decrease. These findings suggest SOCS3 as a potential therapeutic target molecule for protecting photoreceptor cell function during inflammation.

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Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina

栗原 俊英

DIABETES 57 （ 8 ） 2191 - 2198 2008年08月

研究論文（学術雑誌）,  ISSN  0012-1797

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Retinal dysfunction and progressive retinal cell death in SOD1-deficient mice.

栗原 俊英

Am J Pathol. （AMER SOC INVESTIGATIVE PATHOLOGY, INC）  172 （ 5 ） 1325 - 1331 2008年05月

研究論文（学術雑誌）, 査読有り,  ISSN  0002-9440

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The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase (SOD1) in Mice leads to many different phenotypes that resemble accelerated aging. The purpose of this study was to examine the morphology and physiology of the sensory retina in Sod1(-/-) mice. The amplitudes of the a- and b-waves of electroretinograms elicited by stimuli of different intensity were reduced in senescent Sod1(-/-) mice, and this reduction in amplitude was more pronounced with increasing age. Retinal morphometric analyses showed a reduced number of nuclei in both the inner nuclear cell layer and outer nuclear cell layer. Electron microscopy revealed swollen cells and degenerated mitochondria in the inner nuclear cell and outer nuclear cell layer of senescent Sod1(-/-) mice indicating necrotic cell death. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed no significant differences in the number of apoptotic cells between Sod1(-/-) and wild-type mice, and activated caspase-3 could not be detected in the retina of Sod1(-/-) mice. In addition to the age-related macular degeneration-like phenotypes previously reported, Sod1(-/-) mice also present progressive retinal degeneration. Our results indicate that Sod1(-/-) mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated retinal degeneration.

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Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina

栗原 俊英

NEUROSCIENCE RESEARCH 61   S220 - S220 2008年

研究論文（学術雑誌）,  ISSN  0168-0102

Suppression of choroidal neovascularization by dendritic cell vaccination targeting VEGFR2.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  48 （ 10 ） 4795 - 4801 2007年10月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. To investigate whether the induction of cellular immunity against vascular endothelial growth factor receptor ( VEGFR) 2 inhibits the development of choroidal neovascularization (CNV).
METHODS. H-2Db-restricted peptide corresponding to amino acids 400 to 408 of VEGFR2 was used as an epitope peptide. Dendritic cells (DCs) were harvested from bone marrow progenitors of C57BL/6 mice. Six-week-old C57BL/6 mice received subcutaneous injections of the epitope peptide-pulsed mature DCs three times at 6-day intervals. After the third immunization, laser photocoagulation was performed to induce CNV. One week after photocoagulation, mice were killed to harvest the choroid and splenocytes. CNV volume was evaluated by volumetric measurements. To confirm the specific immunogenicity of the epitope peptides in C57BL/6 mice, CD8 T cells isolated from harvested splenocytes were restimulated to measure interferon (IFN)-gamma and tumor necrosis factor (TNF)-gamma production through enzyme-linked immunospot assay and ELISA. To determine the T-cell subset responsible for the immunotherapy, mice were intraperitoneally injected with an anti-CD4 or anti-CD8 depletion antibody.
RESULTS. CNV volume was significantly lower in mice immunized with the VEGFR2 epitope peptide than in those not immunized or immunized with a control peptide gp70. Cytokine assays showed the peptide-specific production of IFN-gamma and TNF-alpha from the CD8 T cells in a dose-dependent manner. In vivo depletion of CD8, but not CD4, T cells significantly reversed the suppressive effect of the VEGFR2 peptide-pulsed DC vaccination on CNV to the level observed in nonimmunized or gp70-immunized animals.
CONCLUSIONS. These results indicate that the VEGFR2 peptide-specific induction of cellular immunity inhibits CNV through the cytotoxicity of CD8 T cells. Results of the present study suggested the possibility of DC vaccination targeting VEGFR2 as a novel therapeutic strategy for CNV.

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Eicosapentaenoic acid is anti-inflammatory in preventing choroidal neovascularization in mice.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  48 （ 9 ） 4328 - 4334 2007年09月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. To investigate the role of eicosapentaenoic acid (EPA), the major omega-3 polyunsaturated fatty acid (PUFA), in the development of choroidal neovascularization (CNV), together with underlying molecular mechanisms.
METHODS. Six-week-old C57BL/ 6 mice were fed with laboratory chow with 5% EPA or the omega-6 PUFA linoleic acid ( LA) for 4 weeks. Laser photocoagulation was performed to induce CNV, and the volume of CNV tissue was evaluated by volumetric measurements. The expression and production of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, vascular endothelial growth factor ( VEGF) and interleukin (IL)-6 in the retinal pigment epithelium (RPE)-choroid in vivo, and stimulated b-End3 endothelial cells and RAW264.7 macrophages in vitro were evaluated by RT-PCR and ELISA. Fatty acid composition in the serum and the RPE-choroid was analyzed by gas chromatography and high-performance liquid chromatography, respectively. Serum levels of C-reactive protein (CRP), IL-6, VEGF, MCP-1, and soluble ICAM-1 were examined by ELISA.
RESULTS. The CNV volume in EPA-fed animals was significantly suppressed compared with that in control mice, whereas the LA-rich diet did not affect CNV. The mRNA expression and protein levels of ICAM- 1, MCP-1, VEGF, and IL- 6 after CNV induction were significantly reduced in EPA-supplemented mice. In vitro, EPA application led to significant inhibition of mRNA and protein levels of ICAM- 1 and MCP-1 in endothelial cells and VEGF and IL- 6 in macrophages. EPA- fed mice exhibited significantly higher levels of EPA and lower levels of the omega-6 PUFA arachidonic acid in the serum and the RPE-choroid than control animals. EPA supplementation also led to significant reduction of serum levels of IL- 6 and CRP after CNV induction.
CONCLUSIONS. The present study demonstrates for the first time that an EPA- rich diet results in significant suppression of CNV and CNV-related inflammatory molecules in vivo and in vitro. These results suggest that frequent consumption of omega-3 PUFAs may prevent CNV and lower the risk of blindness due to age-related macular degeneration.

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Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization.

栗原 俊英

Am J Pathol. （AMER SOC INVESTIGATIVE PATHOLOGY, INC）  170 （ 6 ） 2149 - 2158 2007年06月

研究論文（学術雑誌）, 査読有り,  ISSN  0002-9440

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Interleukin (IL)-6, a potent proinflammatory cytokine, is suggested to be a risk factor for choroidal neovascularization (CNV) because of its increased levels in the serum of patients with age-related macular degeneration; however, the role of IL-6 in CNV has not been defined. The present study reveals the critical contribution of IL-6 signaling and its downstream STAT3 pathway to the murine model of laser-induced CNV. CNV induction by laser treatment stimulated IL-6 expression in the retinal pigment epithelium-choroid complex, and antibody-based blockade of M-6 receptor or genetic ablation of M-6 led to significant suppression of CNV. CNV generation was accompanied by STAT3 activation in choroidal endothelial cells and macrophages, and M-6 receptor blockade resulted in selectively inhibited phosphorylation of STAT3 but not extracellular signal-regulated kinase 1/2. Consistently, pharmacological blockade of STAT3 pathway also suppressed CNV. in addition, M-6 receptor neutralization led to significant inhibition of the in vivo and in vitro expression of inflammation-related molecules including monocyte chemotactic protein, intercellular adhesion molecule-1, and vascular endothelial growth factor, and of macrophage infiltration into CNV. These results indicate the significant involvement of H,6 receptor-mediated activation of STAT3 inflammatory pathway in CNV generation, suggesting the possibility of M-6 receptor blockade as a therapeutic strategy to suppress CNV associated with age-related macular degeneration.

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SOCS3 is required to temporally fine-tune photoreceptor cell differentiation.

栗原 俊英

Dev Biol. （ACADEMIC PRESS INC ELSEVIER SCIENCE）  303 （ 2 ） 591 - 600 2007年03月

研究論文（学術雑誌）, 査読有り,  ISSN  0012-1606

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Suppressor of cytokine signaling 3 (SOCS3) is an intracellular, ligand-induced negative feedback modulator of STAT3 activation that acts during inflammation. Here, we dernonstrate that SOCS3 expression is important for normal retinal development in the perinatal period. STAT3 is highly activated in the late-embryonic retina, then downregulated at postnatal day 0 (PO), presumably by the depletion of upstream ligands. We found that SOCS3 was required after PO to shut down the residual STAT3 activation; this loss of activated STAT3 leads to Rhodopsin expression and rod photoreceptor cell differentiation. SOCS3 deficiency failed to terminate STAT3 activation, thereby delaying expression of Rhodopsin and its upstream transcription factor, crx. Development subsequently continued, but its course was temporally erratic, probably because of faulty compensation. Interestingly, SOCS3 protein expression was first detected postnatally, after STAT3 activation was mostly downregulated. It initially appeared in some of the presumptive photoreceptor cells and gradually spread. SOCS3 mRNA level was constant from the late-embryonic to early-postnatal period. Post-transcriptional inhibition of SOCS3 protein expression maintains a high STAT3 activation during late embryogenesis, and after PO, releasing from the inhibition promptly terminates STAT3 activation. Thus, SOCS3 can act as a temporal fine-tuner of STAT3 activation during photoreceptor cell differentiation. (c) 2006 Elsevier Inc. All rights reserved.

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Neuroprotective effects of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation.

栗原 俊英

Invest Ophthalmol Vis Sci. （ASSOC RESEARCH VISION OPHTHALMOLOGY INC）  47 （ 12 ） 5545 - 5552 2006年12月

研究論文（学術雑誌）, 査読有り,  ISSN  0146-0404

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PURPOSE. To investigate the retinal neural damage that occurs during inflammation and the therapeutic effects of the angiotensin II type 1 receptor (AT1R) blocker, telmisartan, using a model of endotoxin- induced uveitis (EIU).
METHODS. The localization of AT1R and AT2R was shown by immunohistochemistry. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Animals were treated with telmisartan for 2 days and were evaluated 24 hours later. Expression levels of angiotensin II, STAT3 activation induced by inflammatory cytokines, and retinal proteins essential for neural activities (e. g., synaptophysin, rhodopsin) were analyzed by immunoblot. An AT2R antagonist was administered to evaluate the contribution of AT2R signaling in this therapy. Dark-adapted full-field electroretinography ( ERG) was also performed.
RESULTS. AT1R and AT2R were expressed in presynaptic terminals in most of the retinal neurons. AT1R was also expressed in Muller glial cells. During inflammation, angiotensin II expression was elevated, STAT3 was activated, and synaptophysin and rhodopsin expression were reduced. The expression of glial fibrillary acidic protein (GFAP), downstream of STAT3 activation, was induced in Muller glial cells. However, treatment with telmisartan successfully avoided all these changes. An AT2R antagonist lowered synaptophysin expression despite the treatment. STAT3 activity was negatively correlated with rhodopsin expression. Furthermore, ERG responses, which were mostly prevented by telmisartan, were disturbed during inflammation.
CONCLUSIONS. Retinal protein expression and visual function are both disturbed by inflammation. Treatment with the AT1R blocker telmisartan efficiently prevented these signs of retinal neural damage through the reduction of local angiotensin II expression, the blockade of AT1R, and the relative upregulation of AT2R function.

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Pars plana vitrectomy with internal limiting membrane removal for macular hole associated with proliferative diabetic retinopathy.

Kurihara T, Noda K, Ishida S, Inoue M†

Graefes Arch Clin Exp Ophthalmol. （SPRINGER）  243 （ 7 ） 724 - 726 2005年01月

筆頭著者, 査読有り,  ISSN  0721-832X

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Background: We describe the outcome of vitreous surgery in three eyes of three patients with macular hole associated with proliferative diabetic retinopathy (PDR) in the absence of fibrovascular proliferation, a combination of conditions where efficacy is incompletely known. Methods: The patients, all male were 62, 65, and 66 years old. Panretinal photocoagulation had been performed preoperatively in all, and one eye had undergone vitreous surgery. No fibrovascular tissue causing macular traction was observed in any case. Fluorescein angiography and optical coherence tomography (OCT) demonstrated persistent diabetic macular edema surrounding the hole. Affected eyes were treated with vitrectomy including internal limiting membrane (ILM) peeling; 20% sulfur hexafluoride gas (SF6) was introduced for tamponade. Results: Anatomical closure of the macular hole as well as resolution of macular edema was achieved in all cases, and vision improved considerably by more than two Snellen lines. Conclusions: Vitreous surgery with ILM peeling was effective for macular hole associated with PDR, attaining not only macular hole closure but also resolution of persistent diabetic macular edema.

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黄斑パッカーと後天性網膜分離症を合併した網膜剥離の1例

'栗原俊英, 篠田肇, 江下忠彦, 北村静章, 篠田啓, 井上真, 緒方雅郎 '

眼科臨床医報 98 （ 3 ） 205-208 - 208 2004年03月

研究論文（学術雑誌）, 共著